Apical abscission (AA) describes a recently observed process whereby neuroepithelal cells detach from the ventricular lining of the cortex, leaving an abscissed fragment at the apical membrane and releasing a newly formed migratory neuron/ intermediate progenitor to migrate into the cortical plate. This step is required for neuronal proliferation, initial migration from the ventricular zone, and maintenance of tissue architecture along the neuroependyma. Disruption of this process contributes to periventricular heterotopia (PH), a malformation of cortical development characterized by a smaller brain (impaired proliferation), abnormal neurons clustered deep in the brain along the lateral ventricles (failed migration) and loss in neuroependymal integrity (lost tissue architecture). The mechanisms that govern AA are not known. Given the shared features between AA in normal development and PH in disease, we hypothesize that genes causal for PH regulate AA. We have identified several genes causal for PH, including the actin binding Filamin A (FLNA) and vesicle trafficking associated ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes. In our preliminary data, we have identified a novel FlnA binding protein, Fmn2, which has been implicated in both actin regulation and endosomal trafficking. Disruption of Fmn2 causes the same defects in neocortical brain development in mice, similar to that seen with loss of FlnA and Big2. We have engineered Fmn2 knockout mice and Fmn2-FlnA double knockout mice, as well as developed techniques for transient over-expression/ inhibition of these various genes by in utero electroporation. In Aim1, we will determine what steps in AA (timing, cell polarity, cell fat, cell adhesion, actin) are affected by disruption of PH genes using wide field timed lapse microscopy on ex-vivo embryo slice cultures from knockout mice and following in utero electroporation. In Aim2, we will investigate step-wise interactions between the various PH genes in regulation of AA, through in utero electroporation of various PH gene constructs in constitutively active/inactive states or following over- expression/ inhibition. In Aim3, we will examine whether the proliferative changes seen following disruption of PH associated genes is a result of impaired AA.